Benign Enlargement of Subarachnoid Space in Infancy: "A Review with Emphasis on Diagnostic Work-Up".

Macrocephaly is one of the most frequent reasons for referral to a pediatric neurologist. Benign enlargement of subarachnoid space (BESS) in infancy is the most common cause of macrocephaly and characterized clinically with large head circumference, normal or mildly motor and language delay and increased cerebrospinal fluid (CSF) in the subarachnoid space with normal ventricles or mild ventriculomegaly. In this review, we describe the etiology, epidemiology, clinical presentation, pathogenesis, neuroimaging, differential diagnosis, treatment and outcome of this entity from current literature with emphasis on diagnostic work-up.


Introduction
Large head (Macrocephaly) means head circumference more than two standard deviations above the mean for age, sex, and body size, established using measurements and a standard growth chart (1). About 2% of normal population has macrocephaly (1,2). The causes of a large head include hydrocephalus (an excess volume of CSF intracranially), megalencephaly (enlargement of the brain), thickening of the skull and hemorrhage or nonbloody fluid into the subdural or epidural spaces (1,2). Macrocrania in infancy can be due to both benign and pathologic causes. Pathologic cases are rare, alternatively, benign macrocrania of infancy is more common (3). External hydrocephalus is the most common cause of macrocephaly in infants (2)(3)(4). It is a condition in infants and children with enlarged subarachnoid space accompanied by increasing head circumference with normal or mildly dilated ventricles (4, 5). BESS is the most common cause of macrocephaly in infancy (4,8,9). It is more common in males (4, 10, 11). A genetic cause is likely in some cases, with the infants' father often having a large head (3,12). Enlarging extra-axial fluid space is leading to an expansion of head circumference around 3 to 12 months of age, with head circumference measurement crossing percentile lines and often reaching above the 90th-98th percentile ( Figure 1) (2,3,13). Mean age at presentation was 7.3 months (14). Head circumference at birth is normal (2,13,15) or slightly higher than normal (14,15). Autosomal dominant (3,4,15) and multifactorial model of inheritance have been assumed (4, 8, 16).

Epidemiology
An incidence of 0.4 per 1000 live births was reported only in one study (8). It is approximately 50% of hydrocephalic condition in retrospective and population based study in Norway (14).

A review of incidental findings in a tertiary
pediatric neurology center showed that 0.6% of the children had external hydrocephalus (15).

Historical notes
Initially intracranial fluid collections in infants were described in 1850s (17). The term benign external hydrocephalus (BEH) was first introduced in 1917 (7, 17,18). Recently, the most usual name is BESS.

Clinical manifestations
The main feature of BESS is macrocephaly in a normal infant (2,(13)(14)(15)). An otherwise normal infant is referred to medical attention because enlarging head size. Most studies report no signs and symptoms of increased intracranial pressure such as irritability, lethargy, vomiting, tense and bulging anterior fontanel (2,3,5). Rare studies reported a tense anterior fontanel (19,20), dilated scalp veins (21), and frontal bossing (22). Sunset sign is not reported in any article (4). Neurologic findings are normal, but mild motor delay is often seen and final developmental status is often normal 15,16,23).

Pathophysiology
The most accepted theory about pathophysiology of external hydrocephalus is delayed maturation of the arachnoid villi not able to absorb the CSF produced continuously (3,24). Expansion of subarachnoid space due to excessive amount of circulatory CSF is not leading to intracranial hypertension (24,25). Maturation of arachnoid villi occurs in 18 months of age and the process was ended. There is the discrepancy between the skull and brain parenchymal growing which leading to a transient subarachnoid space enlargement (8, 26). On the other hand, external hydrocephalus may be associated with some conditions such as; hypomagnesemia, mucopolysaccharidosis, achondroplasia, agenesis of corpus callosum, sotos syndrome and glutamic aciduria (4, 7, 27, 28).

Differential Diagnosis
1. Brain Atrophy: Is the first and important differential diagnosis because of presence of subdural fluid collection in both conditions (3, 6, 7). In brain atrophy, CSF collection remains equal anteriorly and posteriorly but in BESS larger anterior convexity collections were seen (3, 5, 6).
There is global widening of cerebral sulci in brain atrophy not associated with an increasing head circumference (28).

Benign Familial megalencephaly: This familial
condition is benign and head circumference may be normal at birth but increases during infancy and ultimately should be above 98th percentile. Sotos syndrome and Glutaric aciduria type 1 (32).

Neuroimaging & Diagnostic work up
Neuroimaging findings are one of the criteria for the diagnosis of external hydrocephalus (7).
The first step in confronting with an infant with macrocephaly is doing brain sonography via anterior fontanel (1,33). This modality is fast, safe and non expensive tool used worldwide. Technical CCW, SCW and IHD are from 4 mm to 10 mm, 2 mm to 10 mm and 6 mm to 8.5 mm, respectively (7, 9, 26, 34).

Figure 2: Main neuroradiological criteria for BESS evaluation: A) inter-hemispheric fissure; B) sinocortical width; C) cranio-cortical width (Schematic view).
The second step in evaluation of infant with abnormal brain sonography is brain CT scan or brain MRI (1,7,15,17). Recently use of CT scan is limited because of its radiation and probable risk of malignancies especially in infants and young children (35,36). MRI appears essential in the differential diagnosis between benign enlargement of subarachnoid space and subdural collection in infants and preferred to CT (37)(38)(39). CT and MRI without contrast are also important for evaluating the most common complications associated with external hydrocephalus (7, 38, 39) (Figure 3).

Benign Enlargement of Subarachnoid Space in Infancy: "A Review with Emphasis on Diagnostic Work-Up"
There is a very important note in diagnostic work up of BESS. Repeated imaging is unnecessary unless head growth deviates from the normal curve, neurological examination is abnormal, or social and language development are slow (2,3,13,15,17,20,33).
Final diagnostic note: Patients with typical findings in brain ultrasonography suggestive of external hydrocephalus with normal neurodevelopment without any complications and focal neurologic findings do not require subsequent brain CT / MRI (40)(41)(42).

Complications
The most common complication of BESS in infants and young children is increased risk of subdural hematoma after minimal or even without head trauma (3, 4, 12).
The symptoms related to increased intracranial pressure which often can be seen initially, all appear to be absent at long-term follow-up (4).
Generally the developmental delays are transient
A few old articles suggested use of a carbonic anhydrase inhibitor (Acetazolamide) for few weeks. Acetazolamide therapy for 4-8 wk in 125 mg/bd was recommended (22,23,45). This drug decreases CSF production (6, 23,24,45). There is no clear evidence of effectiveness of this agent in final outcome because of excellent nature of disease (25). Most patients do not need neurosurgical intervention (3, 4) and ventricular shunts (2,18,25,45).